Project Summary: Complex organisms have hundreds of specialized cell types or fates, all of which remarkably derive from the same genetic material, all beginning with a single fertilized egg. As the organism develops, pluripotent cells differentiate, ultimately undergoing progressive lineage restriction and ending with cells that have adopted a specialized cell identity or fate that will be faithfully maintained. To date, many studies have uncovered families of genes whose expression is linked to specific cell types and have identified morphogens and other factors that stimulate specific lineage genes; however, these studies and models cannot explain the expansive diversity achieved with only a limited pool of morphogens and do not address how cells maintain identity through cell divisions or chronologic time. To fully understand how lineage restriction occurs requires much deeper understanding of how cellular competence is achieved ? that is, the ability of a cell to respond to stimuli and differentiate or maintain established identity. We propose that spatial organization of the genome at the nuclear lamina underlies cellular competence during development, thereby instructing establishment of cellular identity. We hypothesize that disruption of spatial genome organization in differentiated cells results in a loss of cellular memory, manifested as aberrant cellular competence, thus critical for maintenance of cellular identity. Our preliminary studies demonstrate that chromatin organization at the lamina may involve distinct compartmentalization. We hypothesize that establishment and maintenance of cellular identity in development and adulthood, respectively, is regulated by distinct molecular and functional compartments of peripheral heterochromatin. We will define the 1) DNA within, 2) epigenetic signature of, and 3) molecular players regulating distinct compartments of peripheral heterochromatin at the nuclear lamina. This work will allow us to uncover the rules governing locus localization, determine the physiological impact of this organization, and reveal how genome organization directs organogenesis.